Molekulárně cytogenetická diagnostika marker chromozomů

• Thesis title in Czech: Molekulárně cytogenetická diagnostika marker chromozomů
• Thesis title in English: Molecular-cytogenetic diagnostics of marker chromosomes
• Key words: marker chromozom, fluorescenční in situ hybridizace, mozaicismus, korelace genotyp-fenotyp, prenatální diagnostika
• English key words: marker chromosome, fluorescence in situ hybridization, mosaicism, phenotype-genotype correlation, prenatal diagnostics
• Academic year of topic announcement: 2009/2010
• Thesis type: dissertation
• Thesis language: čeština
• Department: Department of Biology and Medical Genetics (13-716)
• Supervisor: RNDr. Eduard Kočárek, Ph.D.
• Author: hidden - assigned and confirmed by the Study Dept.
• Date of registration: 02.09.2014
• Date of assignment: 02.09.2014
• Confirmed by Study dept. on: 02.09.2014
• Date and time of defence: 12.09.2018 14:00
• Date of electronic submission: 26.06.2018
• Date of submission of printed version: 26.06.2018
• Date of proceeded defence: 12.09.2018
• Opponents: doc. RNDr. Zuzana Zemanová, CSc.

References

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Preliminary scope of work

Nadpočetné marker chromozomy (sSMC) jsou relativně vzácným cytogenetickým fenoménem. Jejich laboratorní analýza není jednoduchá, a ještě náročnější je klinická interpretace výsledků. Hlavním důvodem je především to, že většina nosičů sSMC nemá žádné klinické projevy. Svoji roli hraje chromozomový původ a přesný rozsah aberace, ale také to, že se sSMC velmi často nacházejí v mozaice, která může ovlivňovat fenotyp i interpretaci výsledků. Prenatální nález sSMC představuje jednu z nejnáročnějších situací v klinické, ale i laboratorní genetice.
Práce se zabývá vyšetřovacím procesem při nálezu sSMC s použitím molekulárně cytogenetických technik, zejména fluorescenční in situ hybridizace (FISH). Prospektivně i retrospektivně bylo vyšetřeno celkem 67 rodin a bylo nalezeno 70 jedinečných sSMC u celkem 74 osob. Šest případů bylo familiárních a ve třech případech byly nalezeny dva sSMC u jednoho jedince. Podle vstupního nálezu v karyotypu byly případy rozděleny do dvou skupin, na sSMC nadpočetné k normálnímu karyotypu (skupina A) a sSMCT nadpočetné k turnerovskému karyotypu (skupina B).
Chromozomový původ byl úspěšně stanoven u 88,6 % sSMC. Ve skupině A byly nejčastějším nálezem sSMC pocházející z chromozomu 15, na druhém místě pak sSMC pocházející z ostatních akrocentrů. Klinické hodnocení vlivu sSMC na fenotyp pacienta jsme uzavřeli u 79,6 % sSMC, z toho jsme v 53,5 % případů hodnotili sSMC jako pravděpodobně patogenní ve vztahu k fenotypu pacienta. Nejčastější indikace k vyšetření v této skupině byly vrozené vývojové vady a/nebo vývojové opoždění a/nebo intelektová nedostatečnost a poruchy reprodukce. U těchto osob se obecně sSMC nacházejí několikrát častěji než v běžné populaci. Ve skupině B byly všechny sSMC podle teoretických očekávání odvozené od gonozomů a svým nosičům způsobovaly příznaky ze spektra Turnerova syndromu a gonadální dysgeneze.
Práce přispívá ke korelaci genotypu a fenotypu u nosičů sSMC, poskytuje vodítka k interpretaci podobných nálezů u dalších pacientů a upozorňuje na netypické případy. Zvláštní pozornost byla věnována specifikům v prenatální diagnostice. U patogenních sSMC byly studovány mechanismy a geny, které mohou k abnormálnímu fenotypu přispívat. V rámci práce jsme také potvrdili význam FISH ve vyšetřovacím schématu, a zejména pro prenatální diagnostiku jsme modifikovali a zefektivnili dosud používaný vyšetřovací algoritmus.

Preliminary scope of work in English

Supernumerary marker chromosomes (sSMCs) are a relatively rare cytogenetic phenomenon. Their laboratory examination is often difficult, and the clinical interpretation is even more challenging. The main reason is that most sSMC carriers have no clinical manifestations. The chromosome origin and exact range of the aberration are very important, as well as the fact that sSMCs are often found in mosaics that can strongly influence both the phenotype and the interpretation of result. Prenatal sSMC finding is one of the most challenging situations in both clinical and laboratory genetics.
This work deals with the investigation process of sSMC carriers using molecular cytogenetic techniques, especially fluorescence in situ hybridization (FISH). We investigated a total of 67 families collected both prospectively and retrospectively, and we found 70 unique sSMCs in a total of 74 individuals. Six cases were familial and in three cases two sSMCs were found in one individual. According to the initial karyotype finding, the cases were divided into two groups, sSMCs supernumerary to a normal karyotype (group A) and sSMCTs supernumerary to the Turner karyotype (group B).
The chromosomal origin was successfully determined in 88,6 % sSMCs. In group A the most common findings were sSMCs derived from chromosome 15, and those derived from other acrocentrics. Clinical evaluation of the effect of the sSMC on phenotype of the patient was concluded in 79,6 % of sSMCs, of which 53,5 % were evaluated as probably pathogenic for at least some abnormalities of the patient. The most common indications for examination in this group were the presence of congenital malformations and/or developmental delay and/or intellectual disability, and reproductive disorders. In these individuals sSMCs are generally found several times more frequently than in the general population. In group B, all sSMCs were, in accord with theoretical expectations, derived from gonosomes, and caused Turner syndrome features and gonadal dysgenesis in their carriers.
The work contributes to the genotype-phenotype correlation in sSMC carriers, provides guidance to interpretation of similar findings in future patients, and points out atypical cases. Particular attention was paid to the specifics of prenatal diagnosis. In pathogenic sSMCs, mechanisms and genes have been studied which can contribute to the abnormal phenotype. We have also confirmed the importance of FISH in the diagnostic scheme, and we have modified the investigation algorithm, especially for prenatal diagnostics.